Real-time self-calibrating sensor system and method

ABSTRACT

A system and method for calibrating a sensor of a characteristic monitoring system in real time utilizes a self-calibration module for periodic determination of, and compensation for, the IR drop across unwanted resistances in a cell. A current-interrupt switch is used to open the self-calibration module circuit and either measure the IR drop using a high-frequency (MHz) ADC module, or estimate it through linear regression of acquired samples of the voltage across the sensor&#39;s working and reference electrodes (Vmeasured) over time. The IR drop is then subtracted from the closed-circuit value of Vmeasured to calculate the overpotential that exists in the cell (Vimportant). Vimportant may be further optimized by subtracting the value of the open-circuit voltage (Voc) across the sensor&#39;s working and reference electrodes. The values of Vmeasured and Vimportant are then controlled by respective first and second control units to compensate for the IR drop.

RELATED APPLICATION DATA

This is a continuation of application Ser. No. 11/323,216, filed Dec.30, 2005, now U.S. Pat. No. ______.

FIELD OF THE INVENTION

This invention relates generally to subcutaneous and implantable sensordevices and, in particular embodiments, to methods and systems forproviding real-time self-calibrating sensor devices.

BACKGROUND OF THE INVENTION

Over the years, a variety of electrochemical sensors have been developedfor detecting and/or quantifying specific agents or compositions in apatient's blood. For instance, glucose sensors have been developed foruse in obtaining an indication of blood glucose levels in a diabeticpatient. Such readings are useful in monitoring and/or adjusting atreatment regimen which typically includes the regular administration ofinsulin to the patient.

Generally, small and flexible electrochemical sensors can be used toobtain periodic readings over an extended period of time. In one form,flexible subcutaneous sensors are constructed in accordance with thinfilm mask techniques in which an elongated sensor includes thin filmconductive elements encased between flexible insulative layers ofpolyimide sheets or similar material. Such thin film sensors typicallyinclude a plurality of exposed electrodes at one end for subcutaneousplacement with a user's interstitial fluid, blood, or the like, and acorresponding exposed plurality of conductive contacts at another endfor convenient external electrical connection with a suitable monitoringdevice through a wire or cable. Typical thin film sensors are describedin commonly assigned U.S. Pat. Nos. 5,390,671; 5,391,250; 5,482,473; and5,586,553 which are incorporated by reference herein. See also U.S. Pat.No. 5,299,571.

These electrochemical sensors have been applied in a telemeteredcharacteristic monitor system. As described, e.g., in commonly-assignedU.S. Pat. No. 6,809,653, the entire contents of which are incorporatedherein by reference, the telemetered system includes a remotely locateddata receiving device, a sensor for producing signals indicative of acharacteristic of a user, and a transmitter device for processingsignals received from the sensor and for wirelessly transmitting theprocessed signals to the remotely located data receiving device. Thedata receiving device may be a characteristic monitor, a data receiverthat provides data to another device, an RF programmer, a medicationdelivery device (such as an infusion pump), or the like.

Regardless of whether the data receiving device (e.g., a glucosemonitor), the transmitter device, and the sensor (e.g., a glucosesensor) communicate wirelessly or via an electrical wire connection, acharacteristic monitoring system of the type described above is ofpractical use only after it has been calibrated based on the uniquecharacteristics of the individual user. According to the current stateof the art, the user is required to externally calibrate the sensor.More specifically, and in connection with the illustrative example of adiabetic patient, the latter is required to utilize a finger-stick bloodglucose meter reading an average of two-four times per day for theduration that the characteristic monitor system is used. Each time,blood is drawn from the user's finger and analyzed by the blood glucosemeter to provide a real-time blood sugar level for the user. The userthen inputs this data into the glucose monitor as the user's currentblood sugar level which is used to calibrate the glucose monitoringsystem.

Such external calibrations, however, are disadvantageous for variousreasons. For example, blood glucose meters are not perfectly accurateand include inherent margins of error. Moreover, even if completelyaccurate, blood glucose meters are susceptible to improper use; forexample, if the user has handled candy or other sugar-containingsubstance immediately prior to performing the finger stick, with some ofthe sugar sticking to the user's fingers, the blood sugar analysis willresult in an inaccurate blood sugar level indication. Furthermore, thereis a cost, not to mention pain and discomfort, associated with eachapplication of the finger stick.

There is therefore a need for a real-time, self-calibrating sensor thatreduces the frequency of, and potentially eliminates the need for,finger sticks.

SUMMARY OF THE DISCLOSURE

According to an embodiment of the invention, a system for calibrating asensor of a characteristic monitoring system in real time utilizes aself-calibration module for periodic determination of, and compensationfor, the IR drop across unwanted resistances in a cell. Theself-calibration module includes a first control unit having apotentiostat, a second control unit, and a current-interrupt switchconnected between the potentiostat and the sensor's counter electrode.The first control unit uses the potentiostat to ensure that a measuredvoltage across the sensor's working and reference electrodes (Vmeasured)is substantially equal to an input voltage (Vactual) of thepotentiostat. The second control unit aims to ensure that theoverpotential (Vimportant) in the cell is substantially equal to anoptimally desired voltage across the sensor's working and referenceelectrodes (Vset), where the “overpotential” may be defined as theeffective amount of potential that is not consumed by the unwantedresistances and, as such, drives the electrochemical reaction at theworking electrode. In embodiments of the invention, the second controlunit may employ a PID controller to calculate Vactual based onVimportant.

In a particular embodiment of the invention, a method of calibrating thesensor in real time includes obtaining a value for Vmeasured,determining the magnitude of the IR drop, calculating the value ofVimportant by subtracting the magnitude of the IR drop from Vmeasured,and then using the first and second controllers, on a periodic basis, todetermine Vactual based on Vset and Vimportant (i.e., the IR-compensatedvalue of Vmeasured). Alternatively, Vimportant may be measured orapproximated directly as the value of Vmeasured at the time thecurrent-interrupt switch is opened.

In embodiments of the invention, the IR drop may be measured by using ahigh-frequency (i.e., in the MHz range) ADC data-acquisition module topinpoint the value of Vmeasured at the point in time when thecurrent-interrupt switch was opened, and then subtracting this valuefrom Vmeasured for the closed circuit. In an alternative embodiment, themagnitude of the IR drop may be estimated through linear regression ofacquired samples of Vmeasured over time, where the samples are acquiredat a lower rate. In addition, Vimportant may be optimized by alsosubtracting (from Vmeasured) the value of the open-circuit voltage (Voc)across the sensor's working and reference electrodes to account for theinherent potential that exists across these electrodes.

The above-described steps may be repeated on a periodic basis, such thatthe sensor is self-calibrating, without the need for externalcalibration by the user. The repetition period may coincide, forexample, with the delay time between successive samplings of the usercharacteristic being monitored by the characteristic monitoring system.

Other features and advantages of the invention will become apparent fromthe following detailed description, taken in conjunction with theaccompanying drawings which illustrate, by way of example, variousfeatures of embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

A detailed description of embodiments of the invention will be made withreference to the accompanying drawings, wherein like numerals designatecorresponding parts in the several figures.

FIG. 1 is a perspective view illustrating a subcutaneous sensorinsertion set, a telemetered characteristic monitor transmitter device,and a data receiving device embodying features of the invention;

FIG. 2 is an enlarged longitudinal vertical section taken generally onthe line 2-2 of FIG. 1;

FIG. 3 is an enlarged fragmented sectional view corresponding generallywith the encircled region 3 of FIG. 2;

FIG. 4 is an enlarged transverse section taken generally on the line 4-4of FIG. 2;

FIG. 5 shows a potentiostat used in implementing a sensor-calibrationmethod according to an embodiment of the invention;

FIG. 6A shows circuitry, components, and modules for implementing asensor-calibration method according to an embodiment of the invention;

FIG. 6B is block diagram of an ADC data-acquisition module in accordancewith an embodiment of the present invention;

FIG. 7 is a flow chart of the steps taken in implementing asensor-calibration method according to an embodiment of the invention;

FIG. 8 is a flow chart of the steps taken in implementing asensor-calibration method according to an alternative embodiment of theinvention;

FIG. 9 is a plot diagram showing the exponential decay of a measuredvoltage over time; and

FIG. 10 is an enlarged view of the portion of the plot shown in FIG. 9that corresponds to −0.1 msec. ≦t≦+0.6 msec.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following description, reference is made to the accompanyingdrawings which form a part hereof and which illustrate severalembodiments of the present invention. It is understood that otherembodiments may be utilized and structural and operational changes maybe made without departing from the scope of the present invention.

The present invention is described below with reference to flowchartillustrations of methods, apparatus, and computer program products. Itwill be understood that each block of the flowchart illustrations, andcombinations of blocks in the flowchart illustrations, can beimplemented by computer program instructions. These computer programinstructions may be loaded onto a computer or other programmable dataprocessing device (such as a controller, microcontroller, or processor)such that the instructions which execute on the computer or otherprogrammable data processing device will implement the functionsspecified in the flowchart block or blocks. These computer programinstructions may also be stored in a computer-readable memory or mediumthat can direct a computer or other programmable data processing deviceto function in a particular manner, such that the instructions stored inthe computer-readable memory or medium produce an article of manufactureincluding instructions which implement the function specified in theflowchart block or blocks. The computer program instructions may also beloaded onto a computer or other programmable data processing device tocause a series of operational steps to be performed on the computer orother programmable device to produce a computer-implemented process suchthat the instructions which execute on the computer or otherprogrammable device provide steps for implementing the functionsspecified in the flowchart block or blocks presented herein.

As shown in the drawings for purposes of illustration, embodiments ofthe invention are described for use in conjunction with a telemeteredcharacteristic monitor transmitter that is coupled to a sensor set andtransmits data from the sensor set to a characteristic monitor fordetermining body characteristics. The sensor set may be implanted inand/or through subcutaneous, dermal, sub-dermal, inter-peritoneal orperitoneal tissue. In preferred embodiments of the present invention,the sensor set and monitor are for determining glucose levels in theblood and/or body fluids of the user without the use, or necessity, of awire or cable connection between the transmitter and the monitor and, incertain embodiments, between the transmitter and sensor set. However, itwill be recognized that further embodiments of the invention may be usedto determine the levels of other agents, characteristics orcompositions, such as hormones, cholesterol, medication concentrations,pH, oxygen saturation, viral loads (e.g., HIV), or the like. Thetelemetered characteristic monitor system is primarily adapted for usein subcutaneous human tissue. However, still further embodiments may beplaced in other types of tissue, such as muscle, lymph, organ tissue,veins, arteries or the like, and used in animal tissue. Embodiments mayprovide sensor readings on an intermittent or continuous basis.

The telemetered characteristic monitor system 1, in accordance with apreferred embodiment of the present invention includes a percutaneoussensor set 10, a telemetered characteristic monitor transmitter device100, and a characteristic monitor 200. The percutaneous sensor set 10utilizes an electrode-type sensor, as described in more detail below.However, in alternative embodiments, the system may use other types ofsensors, such as chemical based, optical based, or the like. In furtheralternative embodiments, the sensor may be of a type that is used on theexternal surface of the skin or placed below the skin layer of the user.Preferred embodiments of a surface-mounted sensor would utilizeinterstitial fluid harvested from underneath the skin. The telemeteredcharacteristic monitor transmitter 100 generally includes the capabilityto transmit data. However, in alternative embodiments, the telemeteredcharacteristic monitor transmitter 100 may include a receiver, or thelike, to facilitate two-way communication between the sensor set 10 andthe characteristic monitor 200. The characteristic monitor 200 utilizesthe transmitted data to determine the characteristic reading. However,in alternative embodiments, the characteristic monitor 200 may bereplaced with a data receiver, storage and/or transmitting device forlater processing of the transmitted data or programming of thetelemetered characteristic monitor transmitter 100. In furtherembodiments, the telemetered characteristic monitor transmitter 100transmits to an RF programmer, which acts as a relay, or shuttle, fordata transmission between the sensor set 10 and a PC, laptop,Communication-station, a data processor, or the like. Still furtherembodiments of the telemetered characteristic monitor transmitter 100may have and use an input port for direct (e.g., wired) connection to aprogramming or data readout device.

The telemetered characteristic monitor transmitter 100 takescharacteristic information, such as glucose data or the like, from thepercutaneous sensor set 10 and transmits it via wireless telemetry tothe characteristic monitor 200, which displays and logs the receivedglucose readings. Logged data can be downloaded from the characteristicmonitor 200 to a personal computer, laptop, or the like, for detaileddata analysis. In further embodiments, the telemetered characteristicmonitor system 1 may be used in a hospital environment or the like. Thetelemetered characteristic monitor transmitter 100 and characteristicmonitor 200 may also be combined with other medical devices to combineother patient data through a common data network and telemetry system.

FIG. 1 is a perspective view of a subcutaneous sensor set 10 providedfor subcutaneous placement of an active portion of a flexible sensor 12(see FIG. 2), or the like, at a selected site in the body of a user. Thesubcutaneous or percutaneous portion of the sensor set 10 includes ahollow, slotted insertion needle 14, and a cannula 16. The needle 14 isused to facilitate quick and easy subcutaneous placement of the cannula16 at the subcutaneous insertion site. Inside the cannula 16 is asensing portion 18 of the sensor 12 to expose one or more sensorelectrodes 20 to the user's bodily fluids through a window 22 formed inthe cannula 16. In embodiments of the invention, the one or more sensorelectrodes 20 may include a counter electrode, a working electrode, anda reference electrode. See, e.g., FIG. 6A. After insertion, theinsertion needle 14 is withdrawn to leave the cannula 16 with thesensing portion 18 and the sensor electrodes 20 in place at the selectedinsertion site.

In preferred embodiments, the subcutaneous sensor set 10 facilitatesaccurate placement of a flexible thin film electrochemical sensor 12 ofthe type used for monitoring specific blood parameters representative ofa user's condition. Thus, the sensor 12 may monitor glucose levels inthe body, and may be used in conjunction with automated orsemi-automated medication infusion pumps of the external or implantabletype as described in U.S. Pat. Nos. 4,562,751; 4,678,408; 4,685,903; or4,573,994, to control delivery of insulin to a diabetic patient.

Preferred embodiments of the flexible electrochemical sensor 12 areconstructed in accordance with thin film mask techniques to includeelongated thin film conductors embedded or encased between layers of aselected insulative material such as polyimide film or sheet, andmembranes. The sensor electrodes 20 at a tip end of the sensing portion18 are exposed through one of the insulative layers for direct contactwith patient blood or other body fluids, when the sensing portion 18 (oractive portion) of the sensor 12 is subcutaneously placed at aninsertion site. The sensing portion 18 is joined to a connection portion24 that terminates in conductive contact pads, or the like, which arealso exposed through one of the insulative layers. In alternativeembodiments, other types of implantable sensors, such as chemical based,optical based, or the like, may be used.

As is known in the art, the connection portion 24 and the contact padsare generally adapted for a direct wired electrical connection to asuitable monitor 200 for monitoring a user's condition in response tosignals derived from the sensor electrodes 20. Further description offlexible thin film sensors of this general type may be found in U.S.Pat. No. 5,391,250, entitled METHOD OF FABRICATING THIN FILM SENSORS,which is herein incorporated by reference. The connection portion 24 maybe conveniently connected electrically to the monitor 200 or acharacteristic monitor transmitter 100 by a connector block 28 (or thelike) as shown and described in U.S. Pat. No. 5,482,473, entitled FLEXCIRCUIT CONNECTOR, which is also herein incorporated by reference. Thus,in accordance with embodiments of the present invention, subcutaneoussensor set 10 may be configured or formed to work with either a wired ora wireless characteristic monitor system.

The sensor electrodes 20 may be used in a variety of sensingapplications and may be configured in a variety of ways. For example,the sensor electrodes 20 may be used in physiological parameter sensingapplications in which a biomolecule is used as a catalytic agent. Thus,the sensor electrodes 20 may be used in a glucose and oxygen sensorhaving a glucose oxidase enzyme catalyzing a reaction with the sensorelectrodes 20. The sensor electrodes 20, along with a biomolecule orsome other catalytic agent, may be placed in a human body in a vascularor non-vascular environment. For example, the sensor electrodes 20 andbiomolecule may be placed in a vein and subjected to a blood stream, orthey may be placed in a subcutaneous or peritoneal region of the humanbody.

The proximal part of the sensor 12 is mounted in a mounting base 30adapted for placement onto the skin of a user. As shown, the mountingbase 30 is a pad having an underside surface coated with a suitablepressure sensitive adhesive layer 32, with a peel-off paper strip 34normally provided to cover and protect the adhesive layer 32, until thesensor set 10 is ready for use. As shown in FIGS. 1 and 2, the mountingbase 30 includes upper and lower layers 36 and 38, with the connectionportion 24 of the flexible sensor 12 being sandwiched between the layers36 and 38. The connection portion 24 has a forward section joined to theactive sensing portion 18 of the sensor 12, which is folded angularly toextend downwardly through a bore 40 formed in the lower base layer 38.In preferred embodiments, the adhesive layer 32 includes ananti-bacterial agent to reduce the chance of infection; however,alternative embodiments may omit the agent. In the illustratedembodiment, the mounting base is generally rectangular, but alternativeembodiments may be other shapes, such as circular, oval, hour-glass,butterfly, irregular, or the like.

The insertion needle 14 is adapted for slide-fit reception through aneedle port 42 formed in the upper base layer 36 and further through thelower bore 40 in the lower base layer 38. As shown, the insertion needle14 has a sharpened tip 44 and an open slot 46 which extendslongitudinally from the tip 44 at the underside of the needle 14 to aposition at least within the bore 40 in the lower base layer 36. Abovethe mounting base 30, the insertion needle 14 may have a full roundcross-sectional shape, and may be closed off at a rear end of the needle14. Further descriptions of the needle 14 and the sensor set 10 arefound in U.S. Pat. Nos. 5,586,553 and 5,954,643, which are hereinincorporated by reference.

The cannula 16 is best shown in FIGS. 3 and 4, and includes a firstportion 48 having partly-circular cross-section to fit within theinsertion needle 14 that extends downwardly from the mounting base 30.In alternative embodiments, the first portion 48 may be formed with asolid core, rather than a hollow core. In preferred embodiments, thecannula 16 is constructed from a suitable medical grade plastic orelastomer, such as polytetrafluoroethylene, silicone, or the like. Thecannula 16 also defines an open lumen 50 in a second portion 52 forreceiving, protecting and guideably supporting the sensing portion 18 ofthe sensor 12. The cannula 16 has one end fitted into the bore 40 formedin the lower layer 38 of the mounting base 30, and the cannula 16 issecured to the mounting base 30 by a suitable adhesive, ultrasonicwelding, snap fit or other selected attachment method. From the mountingbase 30, the cannula 16 extends angularly downwardly with the firstportion 48 nested within the insertion needle 14, and terminates beforethe needle tip 44. At least one window 22 is formed in the lumen 50 nearthe implanted end 54, in general alignment with the sensor electrodes20, to permit direct electrode exposure to the user's bodily fluid whenthe sensor 12 is subcutaneously placed. Alternatively, a membrane cancover this area with a porosity that controls rapid diffusion of glucosethrough the membrane.

As shown in FIGS. 1 and 2, the telemetered characteristic monitortransmitter 100 is coupled to a sensor set 10 by a cable 102 through aconnector 104 that is electrically coupled to the connector block 28 ofthe connector portion 24 of the sensor set 10. In alternativeembodiments, the cable 102 may be omitted, and the telemeteredcharacteristic monitor transmitter 100 may include an appropriateconnector (not shown) for direct connection to the connector portion 24of the sensor set 10 or the sensor set 10 may be modified to have theconnector portion 24 positioned at a different location, such as, forexample, on the top of the sensor set 10 to facilitate placement of thetelemetered characteristic monitor transmitter over the subcutaneoussensor set 10. In yet another embodiment, the monitor transmitter 100may be combined with the sensor set 10 (or sensor 12) as a single unit.In further embodiments, the telemetered characteristic monitortransmitter 100 may omit the cable 102 and connector 104 and is insteadoptically coupled with an implanted sensor, in the subcutaneous, dermal,sub-dermal, inter-peritoneal or peritoneal tissue, to interrogate theimplanted sensor using visible, and/or IR frequencies, eithertransmitting to, and receiving a signal from, the implanted sensor, orreceiving a signal from the implanted sensor. In yet another alternativeembodiment, the telemetered characteristic monitor transmitter 100 andthe sensor set 10 may communicate wirelessly.

The telemetered characteristic monitor 100 includes a housing 106 thatsupports a printed circuit board 108, batteries 110, antenna 112, andthe cable 102 with the connector 104. In preferred embodiments, thehousing 106 is formed from an upper case 114 and a lower case 116 thatare sealed with an ultrasonic weld to form a waterproof (or resistant)seal to permit cleaning by immersion (or swabbing) with water, cleaners,alcohol or the like. In preferred embodiments, the upper and lower case114 and 116 are formed from a medical grade plastic. However, inalternative embodiments, the upper case 114 and lower case 116 may beconnected together by other methods, such as snap fits, sealing rings,RTV (silicone sealant) and bonded together, or the like, or formed fromother materials, such as metal, composites, ceramics, or the like. Inother embodiments, the separate case can be eliminated and the assemblyis simply potted in epoxy or other moldable materials that is compatiblewith the electronics and reasonably moisture resistant. As shown, thelower case 116 may have an underside surface coated with a suitablepressure sensitive adhesive layer 118, with a peel-off paper strip 120normally provided to cover and protect the adhesive layer 118, until thesensor set telemetered characteristic monitor transmitter 100 is readyfor use.

The monitor transmitter 100 may include a sensor interface (whichconnects with the cable 102), processing electronics, and dataformatting electronics (not shown). In embodiments of the invention, thesensor interface, the processing electronics, and the data formattingelectronics may be formed as separate semiconductor chips. However,alternative embodiments may combine the various semiconductor chips intoa single or multiple customized semiconductor chips.

In preferred embodiments, the telemetered characteristic monitortransmitter 100 provides power to the sensor set 10 through the cable102 and cable connector 104. The power is used to monitor and drive thesensor set 10. The power connection is also used to speed theinitialization of the sensor 12, when it is first placed under the skin.The use of an initialization process can reduce the time for sensor 12stabilization from several hours to an hour or less.

At the completion of the stabilizing process, a reading may betransmitted from the sensor set 10 and the telemetered characteristicmonitor transmitter 100 to the characteristic monitor 200, and then theuser will input a calibrating glucose reading (e.g., by performing afinger stick) into characteristic monitor 200. In alternativeembodiments, a fluid containing a known value of glucose may be injectedinto the site around the sensor set 10, and then the reading is sent tothe characteristic monitor 200 and the user inputs the knownconcentration value, presses a button (not shown) or otherwise instructsthe monitor to calibrate using the known value. During the calibrationprocess, the telemetered characteristic monitor transmitter 100 checksto determine if the sensor set 10 is still connected. If the sensor set10 is no longer connected, the telemetered characteristic monitortransmitter 100 will abort the stabilization process and sound an alarm(or send a signal to the characteristic monitor 200 to sound an alarm).

The characteristic monitor 200 includes a telemetry receiver, aTelemetry Decoder (TD), and a host micro-controller (Host)—not shown—forcommunication with the telemetered characteristic monitor transmitter100. The TD is used to decode a received telemetry signal from thetransmitter device and forward the decoded signal to the Host, which maybe a microprocessor for data reduction, data storage, user interface, orthe like. The telemetry receiver receives the characteristic data (e.g.,glucose data) from the telemetered characteristic monitor transmitter,and passes it to the TD for decoding and formatting. After completereceipt of the data by the TD, the data is transferred to the Host forprocessing, where calibration information, based upon user enteredcharacteristic readings (e.g., finger stick blood glucose readings), isperformed to determine the corresponding characteristic level (e.g.,glucose level) from measurement in the characteristic data (e.g.,glucose data). The Host also provides for storage of historicalcharacteristic data, and can download the data to a personal computer,lap-top, or the like, via a corn-station, wireless connection, modem orthe like. For example, in certain embodiments, the counter electrodevoltage is included in the message from the telemetered characteristicmonitor transmitter 100 and is used as a diagnostic signal. The rawcurrent signal values generally range from 0 to 999, which representssensor electrode current in the range between 0.0 to 99.9 nanoAmperes,and is converted to characteristic values, such as glucose values in therange of 40 to 400 mg/dl. However, in alternative embodiments, larger orsmaller ranges may be used. The values are then displayed on thecharacteristic monitor 200 or stored in data memory for later recall.

In further embodiments of the present invention, the characteristicmonitor 200 may be replaced by a different device. For example, in oneembodiment, the telemetered characteristic monitor transmitter 100communicates with an RF programmer (not shown) that is also used toprogram and obtain data from an infusion pump or the like. The RFprogrammer may also be used to update and program the transmitter 100,if the transmitter 100 includes a receiver for remote programming,calibration or data receipt. The RF programmer can be used to store dataobtained from the sensor 12 and then provide it to either an infusionpump, characteristic monitor, computer or the like for analysis. Infurther embodiments, the transmitter 100 may transmit the data to amedication delivery device, such as an infusion pump or the like, aspart of a closed loop system. This would allow the medication deliverydevice to compare sensor results with medication delivery data andeither sound alarms when appropriate or suggest corrections to themedication delivery regimen. In preferred embodiments, the transmitter100 would include a transmitter to receive updates or requests foradditional sensor data. An example of one type of RF programmer can befound in U.S. Pat. No. 6,554,798, which is herein incorporated byreference.

In use, once the sensor and transmitter have been properly positioned,the user programs the characteristic monitor (or it learns) theidentification of the transmitter 100 and verifies proper operation andcalibration of the transmitter 100. The characteristic monitor 200 andtransmitter 100 then work to transmit and receive sensor data todetermine characteristic levels. Thus, once a user attaches atransmitter 100 to a sensor set 10 (or otherwise initiates communicationtherebetween), the sensor 12 is automatically initialized and readingsare periodically transmitted, together with other information, to thecharacteristic monitor 200.

Once the sensor 12 has been initialized, it must be ensured that thesensor 12, and the overall characteristic monitoring system, remaincalibrated. Heretofore, this goal has been achieved via techniques inwhich a blood glucose meter and multiple blood tests are used to obtainreference glucose values which are then correlated withperiodically-acquired glucose monitor data. Examples of such techniquesmay be found in commonly-assigned U.S. Application Publication No.2005/0027177 and U.S. Pat. Nos. 6,424,847 and 6,895,263, all of whichare herein incorporated by reference. Thus, according to the currentstate of the art, the user is required to externally calibrate thesensor by utilizing a finger-stick blood glucose meter reading anaverage of two-four times per day for the duration that thecharacteristic monitor system is used. As noted previously, there arevarious disadvantages associated with such a technique.

To address these disadvantages, it has been found that, in sensors ofthe kind described herein, sensor sensitivity may decrease as a directresult of an increase in additional resistances that tend to build upbetween the working and reference electrodes. This drift in sensitivity,in turn, has an adverse effect on sensor stability, which necessitatesmore frequent sensor calibrations. Therefore, in order to moreaccurately control and measure the voltage across the electrochemicalreaction being analyzed with a given sensor, and thereby reduce thenecessity and frequency of external calibrations, it is important toremove (i.e., account for) any unwanted potentials which might existacross resistances in the vicinity of the electrodes. Once such unwantedpotentials are accounted for, the sensor can be calibrated moreaccurately, in real time, and with little or no need for continualexternal calibrations by the user.

Accordingly, in an embodiment of the present invention, a first level ofsensor calibration may be implemented with standard potentiostathardware. As shown in FIG. 5, such a potentiostat 300 may include an opamp 310 that is connected in an electrical circuit so as to have twoinputs: Vset and Vmeasured. As shown, Vmeasured is the measured value ofthe voltage between a reference electrode and a working electrode. Vset,on the other hand, is the optimally desired voltage across the workingand reference electrodes. The voltage between the working and referenceelectrodes is controlled by providing a current to the counterelectrode. Thus, when unwanted resistances cause the potential betweenthe working and reference electrodes (i.e., Vmeasured in FIG. 5) todeviate from Vset, the current supply to the counter electrode isadjusted to return the potential to the set potential, therebyre-calibrating the sensor.

However, although the feed-back system of FIG. 5 addresses the build-upof additional resistances between the working and reference electrodes,it does so indirectly by measuring voltages at the various electrodes,as opposed to accounting more directly for the potential (i.e., IR) dropacross any such additional resistances. In addition, the inherentvoltage between the working and reference electrodes (i.e., the“open-circuit” voltage) is not accounted for. In short, the systemdepicted in FIG. 5 allows for a calibration process that isless-than-optimal and, as such, may require that a number ofre-calibrations, including external inputs by the user, be performed ona frequent basis.

In preferred embodiments of the invention, therefore, real-timeself-calibration of the sensor is performed by using an IR compensationtechnique with a current interrupt. In this regard, FIG. 6A shows asensor self-calibration module, including an electrical circuit,components, modules, etc., for implementing a self-calibration methodaccording to an embodiment of the present invention. As shown, theself-calibration module includes a potentiostat 300 having an op amp310. The op amp 310 is connected so as to have two inputs: Vactual andVmeasured. As shown, Vmeasured is the measured value of the voltagebetween a working electrode 320 c and a reference electrode 320 b. Theoutput of the op amp 310 is electrically connected to a counterelectrode 320 a via a current-interrupt switch 315.

It is known that, when the current in the circuit is interrupted, thevoltage at node “V”, where values for Vmeasured are obtained,immediately drops by the amount of voltage across the unwantedresistance, i.e., by an amount equal to the IR drop. The magnitude ofthe IR drop, therefore, may be measured by obtaining the value ofVmeasured while the circuit is still closed, obtaining the value ofVmeasured precisely at the point in time when the current interruptswitch 315 is opened (i.e., t=0), and then subtracting the latter fromthe former. However, in practical terms, once the switch 315 is opened,it takes Vmeasured on the order of micro-seconds to fall by an amountequal to the magnitude of the IR drop. As such, given the presenttechnological limitations, it is often difficult, if not impossible, topinpoint time t=0, and then measure a single value for Vmeasured at timet=0.

In light of the above, embodiments of the present invention utilizealternative methods for obtaining the value of Vmeasured at time t=0.With reference to the flow chart of FIG. 7, a real-time self-calibrationmethod according to one embodiment of the present invention is initiatedat step 380 with acquiring a sample measurement for Vmeasured while thecurrent interrupt switch 315 is closed. Then, in step 382, with theswitch 315 still closed, a sampling sub-routine is started wherein ananalog-to-digital converter (ADC) module 330 having a plurality of ADCsis used to obtain a multiplicity of measurements for Vmeasured. In apreferred embodiment, the Vmeasured samples are obtained by said ADCs ata sample rate of about 1 MHz.

After the sampling sub-routine has been initiated, the switch 315 isopened (step 384). The sampling of Vmeasured, however, continues for aperiod of time after the switch 315 has been opened (step 386). In thisway, a multiplicity of successive measurements are obtained forVmeasured during a pre-determined time period that starts prior to, andends after, the opening of the switch 315. In a preferred embodiment,the pre-determined time period may be about 100 μsecs, and the timedelay between successive ADC measurements may be about 1 μsec. Inaddition, in a preferred embodiment, the multiplicity of measurementsfor Vmeasured may be obtained for the range −1.0V≦Vmeasured≦+1.0V.

FIG. 6B shows, for illustrative purposes, an example of how themultiplicity of Vmeasured samples may be obtained by high-frequency(i.e., in the MHz range) sampling. As shown, a plurality of ADCs 330a-330 n are connected in a circuit such that each ADC receives,successively, a respective sampled value for Vmeasured. Thus, when thesampling sub-routine starts, ADC₁ may receive the first sample, followedby ADC₂ receiving the second sample, ADC₃ receiving the third sample,and so on, until each one of the respective Vmeasured samples has beenreceived by a different (succeeding) ADC. Once the sub-routine hasended, a microprocessor unit (MPU) 338 transmits a signal through a linedecoder 335 to request the sample obtained by a specific ADC. Thus, forexample, a signal with a value of a₀-a₀ would notify ADC, that it shouldtransmit its acquired sample to the MPU 338, while a signal with a valueof a₀-a₁ would notify ADC₂ to transmit its sample to the MPU 338, etc.It should be noted that, as shown by the line “A” in FIG. 6B, only oneADC at a time may transmit its sample value to the MPU 338.

Once the successive ADC measurements have been processed (sequentially)by the MPU 338, the processed data is searched to locate the sample ofVmeasured that was obtained at t=0 (step 388). With this information,the IR Calculation module 340 can then calculate the magnitude of the IRdrop. The latter, however, serves primarily as an intermediate vehiclethrough which the magnitude of another variable of utmost importance,i.e., Vimportant in FIG. 6A, is determined. As can be deciphered fromFIG. 6A, Vimportant is indicative of the voltage that exists across theelectrochemical reaction point. That is, in light of the abovediscussion relating to additional, or unwanted, resistances in the cell,Vimportant is the “over potential” (i.e., the effective amount ofpotential that is not consumed by the unwanted resistances) that drivesthe electrochemical reaction at the working electrode 320 c. Vimportant,therefore, may be obtained by the relation expressed in Equation 1:

Vimportant=Vmeasured−IR(Drop)=Vmeasured_(t=0).  (Eq. 1)

where Vmeasured_(t=0) is the value of Vmeasured at current interrupttime=0, and Vmeasured is the sample value obtained at step 380. Thus, atstep 390 in FIG. 7, the value of Vimportant is set to be equal to thevalue obtained by the ADCs for Vmeasured at t=0.

As noted, the block diagram of FIG. 6A shows the circuitry, components,and modules that drive a sensor-calibration module in accordance withembodiments of the present invention (and in conjunction with a sensorof the type shown, e.g., in FIGS. 1 and 2), to implement an IRcompensation technique. In the sensor-calibration module shown in FIG.6A, the potentiostat 300 acts, essentially, as a first control unit (orsub-module) which is operative to ensure that Vmeasured is substantiallyequal to Vactual, wherein the latter is the second input to thecomparator op amp 310.

The sensor-calibration module, however, may also include a secondcontrol unit (or sub-module) which is operative to ensure thatVimportant is substantially equal to Vset. Vset is the optimally desiredvoltage between the working electrode 320 c and the reference electrode320 b, and may be pre-determined based on the value of currentmeasurement(s) taken at node “A” in FIG. 6A (see also step 396 in FIG.7). In the configuration shown in FIG. 6A for illustrative purposes, thesecond control unit is a proportional-integral-derivative (PID)controller 350. Thus, in this configuration, the IR-compensator portionof the circuit comprises a PID control loop, whereby Vimportant isdriven to equal Vset in such a way as to ensure that Vmeasured equalsVactual. To do this, in step 392, Vactual is computed based on Equation2:

$\begin{matrix}{{Vactual} = {{K_{p}e} + {K_{d}\frac{e}{t}} + {K_{i}{\int{e \cdot {t}}}}}} & \left( {{Eq}.\mspace{14mu} 2} \right)\end{matrix}$

where e is the difference between Vset and Vimportant, t is time, K_(p)is the proportional gain, K_(d) is the differential gain, and K_(i) isthe integral gain. It is noted that the PID controller may beimplemented digitally in software, such that the PID control algorithmmay be run on, e.g., a microprocessor within the second control unit.Depending on the specific sensor type and related circuitry, the controlalgorithm may also be run on the MPU 338, or other computer/processorwithin the sensor-calibration module. It is also noted that adigital-to-analog converter (DAC) module 360 may be employed to convertthe outputted digital signal into an analog input signal to the op amp310.

Once Vactual has been calculated, the current interrupt switch 315 isclosed (step 394), and the sensor is used to obtain a sample of the usercharacteristic that is being monitored by the characteristic monitoringsystem. In FIG. 7, blood glucose (BG) is shown, for purposes ofillustration, as the user characteristic of interest. Thus, once theswitch 315 has been closed, at step 396, a current measurement is takenat point “A” and converted into a blood glucose level (by using, e.g., asingle finger stick to calibrate current measurements for the specificuser).

The algorithm then loops back and resets the sensor-calibration module'stimer (step 398). Again, with the illustrative example of monitoringblood glucose levels in a user, a typical delay time between successiveBG samples may be about five minutes. In a preferred embodiment, it istherefore desirable to have the sensor calibrated at least as frequentlyas the rate of acquisition of BG samples, and just prior to the BGsample being taken. As such, in one embodiment, once the timer has beenreset, a determination is made at step 399 as to whether five minuteshave elapsed since the previous calibration of the sensor. If fiveminutes have passed, then the above-described process is repeated,except that, when step 396 is performed, there is no need for anotherfinger stick, since a correlation between the user's BG level and thesensor's readings has been previously established. If, on the otherhand, it is determined at step 399 that less than five minutes havepassed since the immediately-previous calibration, the algorithm loopsback and re-tries until the elapsed time is equal to five minutes.

As noted previously, Vimportant is indicative of the “over potential”that is available to drive the electrochemical reaction at the workingelectrode 320 c. Thus, the more precise the measurement(s) ofVimportant, the more precise and effective the sensor-calibrationprocess described above. In this regard, it is known that, because theyare made of different materials, the working and reference electrodeshave an inherent voltage between them. A more precise determination ofVimportant, therefore, would attempt to account for this inherentvoltage.

FIG. 8 shows a flow chart that depicts a self-calibration process inaccordance with a more preferred embodiment of the invention. As shown,the process includes the same steps 380, 382, 384, 386, and 388 as thosedescribed in connection with FIG. 7. However, in this alternativeembodiment, in addition to determining the value of Vmeasured at t=0,the inherent voltage noted above is also measured. The inherent voltageis also called the open-circuit voltage (Voc) because its magnitude isobtained by leaving the switch 315 open long enough (e.g., less than 1msec.) for the voltage between the working electrode 320 c and thereference electrode 320 b to stabilize to its steady-state, open-circuitvalue. As this point, Voc is measured (step 389), and Vimportant iscalculated in accordance with Equation 3:

Vimportant=Vmeasured−IR(Drop)−Voc=Vmeasured_(t=0) −Voc.  (Eq. 3)

where, as in Equation 1, Vmeasured_(t=0) is the value of Vmeasured atcurrent interrupt time=0, and Vmeasured is the sample value obtained atstep 380. It is noted that Equation 1 differs from Vactual is computedin accordance with Equation 2 (step 392), where Vset is now defined asthe optimally desired overpotential in the cell. Having the value forVactual, the same steps 394, 396, 398, and 399 as in FIG. 7 are thenfollowed to calibrate the sensor on a real-time basis.

The real-time, self-calibration techniques for IR compensation depictedin FIGS. 7 and 8 require that a relatively high, uniform sampling ratebe used (through the ADC module 330, e.g.) in order to ascertain thevalue of Vmeasured_(t=0). However, depending on the specificapplication, such a sampling rate may be unachievable and/orimpractical. As such, in a alternative embodiment of the presentinvention, the magnitude of the IR drop may be estimated at a lowersampling rate by backwards extrapolation.

More specifically, in this alternative embodiment, a multiplicity ofmeasurements for Vmeasured are still obtained during a time period thatstarts prior to, and ends after, the opening of the switch 315. Thesemeasurements are then plotted against time. As shown in FIG. 9, thevoltage decays in a generally exponential manner. However, experimentshave shown that the decay can be approximated as linear for about thefirst 0.5 milliseconds after the switch has been opened (i.e., untilabout t≈0.5 msec.). As such, an estimate of the decaying gradient canallow for a backwards-in-time extrapolation (to the point in time whenthe switch was opened) with generally as few as two or three samplepoints.

Thus, by way of example, FIG. 9 illustrates the results of an experimentin which samples were acquired at times t≈0.1 msec., t≈0.2 msec., andt≈0.5 msec., and linear regression was performed to backward extrapolateto time t=0 to obtain an approximate value for Vmeasured_(t=0). As shownin the Vmeasured-vs.-time plot, the exponential decay of Vmeasured canbe estimated as linear for approximately the first 0.5 msec., and aregression line generated, such that an estimated value can be obtainedfor Vmeasured at time t=0.

FIG. 10 depicts an enlarged view of the first 0.5 msec. of theVmeasured-vs.-time plot of FIG. 9. For the purposes of the experiment, aVmeasured of 0.525V was observed with the current interrupt switch 315closed. When the switch was opened, Vmeasured dropped to 0.5V beforedecaying exponentially. Therefore, Vmeasured at time t=0 is 0.5V, withan IR drop of 0.025V. Using backwards-in-time extrapolation, aregression line was then calculated as previously described, whichresulted in an estimated Vmeasured_(t)=₀ value of 0.49V, with an IR dropof 0.035V. This resulted in a measurement error of approximately 2%,which may, depending on the specific application, prove to be trivial.Of course, once an approximate value for Vmeasured_(t=0) has beenobtained, the remainder of the self-calibration process is carried outas shown in FIGS. 7 and 8.

In yet other alternative embodiments of the invention, thecurrent-interrupt switch 315 may not be necessary at all. Thus, in onesuch embodiment, the IR drop may be measured by applying AC signals tothe cell and analyzing the effect. More specifically, it is known thattwo resistances exist in series between the working and referenceelectrodes: The unwanted resistance across which the IR drop isobserved, and the faradaic resistance whose potential is equal toVimportant. In parallel with the faradic resistance is a capacitancethat does not exist across the unwanted resistance. With thisconfiguration, high-frequency signals passed between the working andreference electrodes would pass through the above-mentioned capacitancewith no voltage drop, such that the capacitance behaves essentially as ashort circuit. When, on the other hand, low-frequency signals areapplied, the capacitance behaves as an open circuit. Therefore, at highfrequencies, where the faradic capacitance is effectively a shortcircuit, the unwanted resistance would be equal to the applied voltagedivided by the cell current. With the unwanted resistance known, the IRdrop may be calculated at a later time by multiplying the magnitude ofthe resistance by the cell current.

It should be noted that the various alternative embodiments of thepresent invention are not necessarily mutually exclusive, and two ormore self-calibration processes may be carried out together, wherein oneapproach may be used to verify the efficacy of another, or a primary anda secondary approach may be used to provide a redundancy in the system.In addition, one approach, e.g., that depicted in FIG. 7, may be usedfor control purposes (i.e., for real-time self-calibration of thesensor), while a second approach, e.g., that depicted in FIG. 8, is usedfor diagnostic purposes (i.e., to check the status of a sensor, where anexcessive IR drop, for example, would indicate a sensor malfunction), orvice versa.

In addition, embodiments of the present invention have been described inconnection with specific circuit configurations and/or electroniccomponents, modules, sub-modules, etc. However, various alternatives maybe used, all of which are intended to be covered by the claims herein.For example, with reference to FIGS. 1 and 2, in a self-calibratingcharacteristic monitoring system in accordance with embodiments of theinvention, the sensor-calibration module (including any microprocessors,controllers, and associated electronics) may be contained within thehousing 106 of the transmitter device 100. Alternatively, thesensor-calibration module may be contained within the same housing asthat of the sensor 12. In yet a third embodiment, the sensor-calibrationmodule may be contained within the same housing as that of the datareceiving device 200. Moreover, the sensor, the transmitter device, andthe data receiving device may communicate with one another eitherthrough an electrical cable or wirelessly.

Similarly, in various embodiments of the invention described herein, theelectronic circuit has included an operational amplifier for measuringand controlling the voltage between the working and referenceelectrodes. However, any comparator circuit or differential amplifiermay be used in place of the op amp. Specifically, low currenttransistors, such as, e.g., Field effect transistors (FET) and the likemay be utilized to perform these functions.

While the description above refers to particular embodiments of thepresent invention, it will be understood that many modifications may bemade without departing from the spirit thereof. The accompanying claimsare intended to cover such modifications as would fall within the truescope and spirit of the present invention.

The presently disclosed embodiments are therefore to be considered inall respects as illustrative and not restrictive, the scope of theinvention being indicated by the appended claims, rather than theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A system for calibrating a sensor of a characteristic monitoringsystem in real time by determining, and compensating for, an IR dropacross unwanted resistances in a cell, said sensor including a counterelectrode, a reference electrode, and a working electrode incommunication with a user's blood or interstitial fluids to producesignals indicative of said characteristic, the system comprising: afirst control unit having a potentiostat, said potentiostat including anoperational amplifier connected in an electrical circuit to maintainsubstantial equality between the magnitude of a measured voltage acrossthe sensor's working and reference electrodes and the magnitude of anapplied voltage; a current-interrupt switch electrically connectedbetween the operational amplifier's output and the sensor's counterelectrode to provide a closed circuit when the switch is closed and anopen circuit when the switch is opened; and a second control unitincluding a microprocessor and connected in the electrical circuit tomaintain substantial equality between the magnitude of an optimallydesired voltage across the sensor's working and reference electrodes andthe magnitude of an effective amount of potential in the cell thatdrives electrochemical reactions at the working electrode, saideffective amount of potential reflecting an adjustment for the magnitudeof said IR drop, and said second control unit providing said appliedvoltage as an input to the operational amplifier.
 2. The system of claim1, wherein the second control unit calculates the magnitude of saideffective amount of potential in the cell by subtracting the magnitudeof the IR drop from the closed-circuit magnitude of said measuredvoltage across the sensor's working and reference electrodes.
 3. Thesystem of claim 2, wherein the second control unit estimates themagnitude of the IR drop through linear regression of acquiredopen-circuit samples of said measured voltage across the sensor'sworking and reference electrodes over time.
 4. The system of claim 2,wherein the magnitude of said effective amount of potential in the cellis optimized by further subtracting therefrom the magnitude of theopen-circuit voltage across the sensor's working and referenceelectrodes.
 5. The system of claim 4, wherein the magnitude of saidopen-circuit voltage is obtained by allowing, while said switch remainsopen, the voltage between the working and reference electrodes tostabilize to a steady-state value, and then measuring said steady-statevalue.
 6. The system of claim 1, wherein the second control unit is aproportional-integral-derivative (PID) controller.
 7. The system ofclaim 6, wherein the PID controller calculates the magnitude of saidapplied voltage based on the magnitude of said effective amount ofpotential in the cell.
 8. The system of claim 1, further including atransmitter device that is in communication with the sensor to receivesignals therefrom, said transmitter device including a processor toprocess the signals from the sensor and a transmitter for wirelesslytransmitting the processed signals to a data receiving device.
 9. Thesystem of claim 8, wherein the data receiving device is an insulin pump.10. The system of claim 8, wherein said system and said data receivingdevice are contained within a single housing.
 11. The system of claim 1,wherein said system and said sensor are contained within a singlehousing.
 12. The system of claim 1, wherein said characteristic is aglucose level in the body of the user.
 13. The system of claim 1,wherein the sensor is implantable in tissue selected from the groupconsisting of subcutaneous, dermal, sub-dermal, intra-peritoneal, andperitoneal tissue.
 14. The system of claim 1, wherein the sensor is apercutaneous sensor.